Long-term career goals are to: 1) develop a research program to investigate the cellular signaling alterations triggered by host-pathogen interactions relevant to neuro-psychiatric disorders such as HIV-associated Dementia (HAD) and 2) become an independent bio-medical scientist at an academic institution. Detailed career development and scientific plans addressing the potential contribution of highly active anti-retroviral therapy (HAART) to NeuroAIDS is proposed. Shortly after sero-conversion, HIV patients may be prescribed protease inhibitor (PI)-based HAART regimens. HAART has proven highly successful in suppressing systemic viral burden; however, the ATP-dependent efflux transport pump, P-glycoprotein (P-gp), imposes a serious constraint on PI treatment of NeuroAIDS. Because of viral rebound, resistance mutations and the potential interactions of PIs with HIV proteins and cerebral endothelial cells (CEC), the main objective of this proposal is to determine the effects of chronic PI exposure on the CEC's ability to respond to host-derived growth factors, such as fibroblast growth factor 2 (FGF2), that are generated as defense mechanisms against HIV proteins _resent in the blood stream at viral rebound. We hypothesize that long-term exposure to PIs such as saquinavir (SQV), indinavir (INV), nelfinavir (NFV) and/or ritonavir (RTV) will modify P-gp efflux-dependent expression and activity, thereby altering P-gp efflux-independent signaling pathways in the FGF2-mediated caveolin/ERK/NO systems. For this purpose, AIM I will determine the effects of chronic PI treatment on CEC fitness and signaling mediated by FGF2 via interactions with P-gp and caveolin. Four aspects of CEC fitness will be tested: 1) viability, 2) P-gp expression and activity, 3) P-gp-mediated caveolin and endothelial nitric oxide synthase (eNOS) signaling and nitric oxide (NO) production, 4) FGF2-mediated extracellular regulated kinase (ERK) signaling and angiogenic capacity. AIM II will address in vitro, how chronic exposure of CEC to PI disrupts P-gp/caveolin/FGF2-dependent protection from the HIV protein, gp120. Using MSR-gp120 and GFAPFGF2 transgenic mice, AIM III will investigate, in vivo, the long-term effects of chronic PI treatment in disrupting signaling at the blood-brain barrier (BBB) during interaction with HIV proteins. Understanding the mechanisms responsible for alterations in FGF2 signaling via P-gp/caveolae after chronic PI exposure is important for identifying factors that may contribute to the progression of neurological and neurobehavioral alterations associated with NeuroAIDS during viral rebound or at virologic failure.